Physiologically active steroid molecules produced by the body are classified as either "glucocorticoid," "mineralocorticoid," or "sex steroid" depending on their specific activity. The glucocorticoid steroids are defined by the exhibition of two physiological actions-glycogenic and anti-inflammatory. They are glycogenic in that they effect the carbohydrate metabolism and increase gluconeogenesis and they are anti-inflammatory in that they prevent, inhibit, or reduce inflammation. (Ringler, I. "Activities of Adrenocorticosteroid in Experimental Animals and Man." in Dorfman, R. I. (Editor). "Methods in Hormone Research." Volume III, 1964. Academic Press, New York. and David, D. S. et al. 1970, J. Chron. Dis. 22:637-711.) The classification of "glucocorticoid" is usually dependent upon measurement of increased liver glucose concentrations, increased plasma glucose concentrations, and/or anti-inflammatory activity in response to the steroid. It has been found that the glycogenic activity parallels the anti-inflammatory activity of glucocorticoid steroids. (Ringler, I. "Activities of Adrenocorticosteroid in Experimental Animals and Man." in Dorfman, R. I. (Editor) "Methods in Hormone Research." Volume III. 1964. Academic Press, New York., Castles, J. J. "Glucocorticoid." in McCarty, D. J. (Editor). "Arthritis and Allied Conditions." Tenth Edition, 1985. Lea & Febiger, Philadelphia., Thomas, J. A. & Keenan, E. J. "Principles of Endocrine Pharmacology." 1986. Plenum Medical Book Co., New York., Haynes, R. C. "Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones." in Gilman, A. G. et al. (Editors). "The Pharmacological Basis of Therapeutics." Eighth Edition. 1990. Pergamon Press, New York.)
All previously known steroid molecules, naturally occurring or synthetic, that have been shown to exhibit significant anti-inflammatory activity have also exhibited significant and parallel glycogenic activity. (Haynes, R. C. "Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones." in Gilman, A. G. et al. (Editors). "The Pharmacological Basis of Therapeutics." Eighth Edition. 1990. Pergamon Press, New York., and Gill, G. N. "The Adrenal Gland". in West, J. B. (Editor). "Physiological Basis of Medical Practice." Twelfth Edition. 1991. Williams & Wilkins, Baltimore.) It has been thought that these two activities, glycogenic and anti-inflammatory, are firmly linked and it is unlikely that they could be dissociated by changing the chemical structure of the steroid molecule. (Bentley, P. J. "Endocrine Pharmacology." 1980. Cambridge University Press, New York.) Since no substantial progress has previously been reported toward separation of these two activities, it is generally held that they are only different physiological expressions of a common mechanism of action, Since there is experimental evidence suggesting that a single mechanism is responsible for both activities, it has been held unlikely that this long sought after separation of activities could be achieved. (Castles, J. J. "Glucocorticoid." in McCarty, D. J. (Editor). "Arthritis and Allied Conditions." Tenth Edition. 1985. Lea & Febiger, Philadelphia., and Popper, T. L. and Watnick, A. S. "Anti-inflammatory Steroids." in Scherrer, R. A. and Whitehouse, M. W. (Editors). "Anti-inflammatory Agents." Volume I. 1974. Academic Press, New York.)
The major problem with the glucocorticoid as anti-inflammatory agents, however, is their glycogenic activities. These glycogenic adverse side-effects are simply the exaggerated responses to the pharmacologic (supra-physiological) doses. The ideal anti-inflammatory steroid would not exhibit glycogenic activity. The prior art does not permit this anti-inflammatory activity without glycogenic activity.
Since some of the major adverse side-effects of the glucocorticoid are the anticipated glycogenic actions of the supra-physiologic doses, the prior art of their use has resulted in the following six problems or limitations of use: 1 .) frequent occurrence of significant adverse side-effects, 2.) limitations of dosage, 3.) limitation of duration of use, 4.) contraindication for use in certain specific groups of people, 5.) reduced frequency of use, and 6.) restricted route of administration.
Commonly observed adverse side-effects can include the following: adrenal suppression; hyperglycemia and glycosuria ("steroid diabetes mellitus"); myopathy; osteoporosis; skin atrophy; redistribution of body fat (e.g. "buffalo hump"); and delayed wound healing. (Haynes, R. C. "Adrenocorticotropic Hormone." in Gilman, A. C. et al (Editors). "The Pharmacological Basis of Therapeutics." 1990. Pergamon Press, New York; Thomas, J. A. and Keenan, E. J. "Principles of Endocrine Pharmacology." 1986. Plenum Medical Book Co., New York; Bentley, P. J. "Endocrine Pharmacology." 1980. Cambridge University Press, New York; Hart, D. F. "Drug Treatment of the Rheumatic Diseases." 1979. Adis Press, New York.) This is primarily iatrogenic hypercortisolism. In fact, the most common cause of hypercortisolism is the therapeutic use of glucocorticoid. It had been estimated in 1968 that the glucocorticoid were probably the cause of more iatrogenic diseases than any other group of drugs. One estimate of all therapeutic drug deaths in England attributed 20% to the glucocorticoid. (Bentley, P. J. "Endocrine Pharmacology." 1980. Cambridge University Press, New York.)
In an effort to reduce these severe adverse side-effects, the dosage of the glucocorticoid steroids is reduced as much as possible for prolonged use. For example, the initial dose of prednisone, a typical glucocorticoid commonly used in treating inflammation, may be 10 mg/day. But the maintenance dosage may not be greater than 7.5 mg/day. (Weiss, M. M. 1989. Seminars in Arthritis and Rheumatism. 19:9-21.) It is generally accepted that if a dosage of prednisone exceeds 6 to 7 mg/day some adverse side-effects will be exhibited. A dosage of 10 rag/day will invariably result in side-effects within a few weeks or months. (Hart, D. F. "Drug Treatment in the Rheumatic Diseases." 1979. Adis Press, New York.) Therefore, the dosage of glucocorticoid used is limited by the occurrence of adverse side-effects, thus limiting the anti-inflammatory efficacy.
Even very low doses of glucocorticoid administered over prolonged periods of time may have adverse side-effects. It is thought, therefore, that deleterious effects are the result of the total cumulative dose. (Weiss, M. M. 1989. Seminars in Arthritis and Rheumatism. 19:9-21.) Therefore the duration of treatment can be limited by the adverse side-effects. The dose and duration of treatment with glucocorticoid parallel the incidence and severity of adverse side-effects. (Bentley, P. J. "Endocrine Pharmacology." 1980. Cambridge University Press, New York; Castles, J. J. "Glucocorticoid." in McCarty, D. J. (Editor) "Arthritis and Allied Conditions." 1985. Lea & Febiger, Philadelphia.) Therefore, the duration of use of glucocorticoid is limited by the adverse side-effects, thus limiting the anti-inflammatory efficacy.
As a result of pre-existing conditions, the use of glucocorticoid as anti-inflammatory agents are contraindicated in certain individuals. This is often due to the glycogenic activity of the glucocorticoid. Their use is contraindicated due to the glycogenic activity in people with such conditions as the following: diabetes mellitus, osteoporosis, pregnancy, growing children, wound healing, and Cushing's syndrome. (Thomas, J. A. and Keenan, E. J. "Principles of Endocrine Pharmacology." 1986. Plenum Medical Book Co., New York; Bentley, P. J. "Endocrine Pharmacology." 1980. Cambridge University Press, New York; Weiss, M. M. 1989. Seminars in Arthritis and Rheumatism. 19:9-21; Castles, D. J. "Glucocorticoid ." in McCarty, D. J. (Editor) "Arthritis and Allied Conditions." 1985. Lea & Febiger, Philadelphia.) Therefore, even the use of glucocorticoid is contraindicated in some people, thus denying them access to potent anti-inflammatory efficacy.
One method used in the prior art to reduce the incidence and severity of adverse side-effects of glucocorticoid is "Alternate-day dose regimen." Another method is the "single morning dose regimen." These methods of periodic, intermittent, or pulse dosing may reduce some of the glycogenic related adverse side-effects in some, but not all people. In addition, they may reduce the anti inflammatory efficacy of the drug. (Haynes, R. L. "Adrenocorticotropic Hormone": in Gilman, A. G. et al (Editors) "The Pharmacological Basis of Therapeutics." 1990. Pergamon Press, New York; Popper T. L. and Watnick, A. S. "Anti-inflammatory Steroids." in Scherrer, R. A. and Whitehouse, M. W. "Anti-inflammatory Agents." 1974. Academic Press, New York; Hart, F. D. "Drug Treatment of the Rheumatic Diseases." 1979. Adis Press, New York; Bentley, P. J. "Endocrine Pharmacology." 1980. Cambridge University Press, New York; Castles, J. J. "Glucocorticoid." in McCarty, D. J. "Arthritis and Allied Conditions." 1985. Lea & Febiger, Philadelphia.)
Changing the route of administration of glucocorticoid has been used in an effort to reduce the potential for systemic adverse side-effects. While local injections have been used to reduce systemic glycogenic related complications, they have simultaneously increased the probability for other severe adverse side-effects. In addition, local injections continue to produce local adverse side effects related to the glycogenic activity. (Popper, T. L. and Watnick, A. S. "Anti-inflammatory Steroids." in Scherrer, R. A. and Whitehouse, M. W. (Editors) "Anti-inflammatory Agents." 1974. Academic Press, New York; Weiss, M. M. 1989. Seminars in Arthritis and Rheumatism. 19:9-21; David, D. S., Grieco, M. H., and Cushman, P. 1970. J. Chron. Dis. 22:637-711; Hart, D. F. "Drug Treatment of the Rheumatic Diseases." 1979. Adis Press, New York.) Therefore, the route of administration of glucocorticoid is often limited by adverse side-effects, thus limiting the anti-inflammatory efficacy.
A previous patent (U.S. Pat. No. 4,795,747) demonstrated that 16-epiestriol exhibited significant anti-inflammatory activity. Its molecular structure, however, contained none of the four structural elements considered by the prior art essential for anti-inflammatory activity.